rs1126568
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1
The NM_004168.4(SDHA):c.1799G>A(p.Arg600Gln) variant causes a missense change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R600W) has been classified as Uncertain significance.
Frequency
Consequence
NM_004168.4 missense
Scores
Clinical Significance
Conservation
Publications
- hereditary pheochromocytoma-paragangliomaInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- pheochromocytoma/paraganglioma syndrome 5Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- mitochondrial complex II deficiency, nuclear type 1Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
- neurodegeneration with ataxia and late-onset optic atrophyInheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
- Leigh syndromeInheritance: AR Classification: MODERATE Submitted by: Ambry Genetics, ClinGen
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- gastrointestinal stromal tumorInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Leigh syndrome with leukodystrophyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- mitochondrial complex II deficiencyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- dilated cardiomyopathy 1GGInheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.1799G>A | p.Arg600Gln | missense_variant | Exon 14 of 15 | ENST00000264932.11 | NP_004159.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.1799G>A | p.Arg600Gln | missense_variant | Exon 14 of 15 | 1 | NM_004168.4 | ENSP00000264932.6 | ||
ENSG00000286001 | ENST00000651543.1 | n.*532G>A | non_coding_transcript_exon_variant | Exon 13 of 24 | ENSP00000499215.1 | |||||
ENSG00000286001 | ENST00000651543.1 | n.*532G>A | 3_prime_UTR_variant | Exon 13 of 24 | ENSP00000499215.1 |
Frequencies
GnomAD3 genomes AF: 0.0000791 AC: 12AN: 151738Hom.: 0 Cov.: 30 show subpopulations
GnomAD2 exomes AF: 0.0000209 AC: 5AN: 239052 AF XY: 0.0000155 show subpopulations
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000345 AC: 50AN: 1450124Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 29AN XY: 720116 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000790 AC: 12AN: 151856Hom.: 0 Cov.: 30 AF XY: 0.0000808 AC XY: 6AN XY: 74278 show subpopulations ⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
ClinVar
Submissions by phenotype
not provided Uncertain:5
The frequency of this variant in the general population, 0.00015 (3/19410 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with paragangliomas (PMIDs: 28384794 (2018) and 25595276 (2015)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
PP3, PP4 -
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In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27011036, 25595276, 28384794, 30877234) -
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Hereditary cancer-predisposing syndrome Pathogenic:1
The p.R600Q variant (also known as c.1799G>A), located in coding exon 14 of the SDHA gene, results from a G to A substitution at nucleotide position 1799. The arginine at codon 600 is replaced by glutamine, an amino acid with highly similar properties. This variant was reported in individuals with features consistent with hereditary paraganglioma-pheochromocytoma (von Dobschuetz E et al. Endocr. Relat. Cancer, 2015 Apr;22:191-204; Bausch B et al. JAMA Oncol, 2017 Sep;3:1204-1212; Ben Aim L et al. J. Med. Genet., 2019 08;56:513-520; Ambry internal data). The alteration was also detected in two gastrointestinal stromal tumors (GIST), which tested negative for SDHB by immunohistochemistry (Boikos SA et al. JAMA Oncol, 2016 Jul;2:922-8), and was reported as a germline finding in two additional individuals with SDHB-deficient GISTs (Pantaleo MA et al. Front Oncol, 2021 Jan;11:778461). This alteration was also reported in conjunction with a second SDHA variant of unknown significance in a patient with respiratory chain group mitochondrial disease (Wu T et al. Pediatr Neurol, 2022 Jul;132:11-18). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1
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Dilated cardiomyopathy 1GG Uncertain:1
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Pheochromocytoma/paraganglioma syndrome 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported in individuals with SDHA-related conditions (PMID: 25595276, 28384794). ClinVar contains an entry for this variant (Variation ID: 259244). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces arginine with glutamine at codon 600 of the SDHA protein (p.Arg600Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. -
Gastrointestinal stromal tumor Uncertain:1
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Dilated cardiomyopathy 1GG;C3279992:Pheochromocytoma/paraganglioma syndrome 5;C5543254:Neurodegeneration with ataxia and late-onset optic atrophy;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Uncertain:1
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SDHA-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at